Midodrine

Midodrine is an oral prodrug whose active metabolite, desglymidodrine, is a selective alpha 1 agonist. It raises standing blood pressure by arterial and venous constriction and is used for symptomatic neurogenic orthostatic hypotension. Its main hazard is supine hypertension. Off label uses include hepatorenal syndrome and intradialytic hypotension.

Classification. Alpha 1 adrenergic agonist; vasopressor; prodrug.

Mechanism. Desglymidodrine stimulates alpha 1 receptors on arterioles and veins, increasing vascular resistance and venous return. It does not stimulate the heart and does not cross the blood brain barrier.

Pharmacodynamics. Standing systolic pressure rises by about 15 to 30 mmHg within 1 hour, lasting 2 to 3 hours. Reflex bradycardia can occur. Supine pressure also rises, so timing of doses matters.

Pharmacokinetics. Oral bioavailability about 93% as desglymidodrine; peak at 1 to 2 hours; elimination half life of the active metabolite about 3 to 4 hours. Excreted mainly by the kidney, partly by active tubular secretion.

Symptomatic neurogenic orthostatic hypotension, adult.

• Start 2.5 mg orally three times daily.

• Increase by 2.5 mg a dose each week to the usual range of 5 to 10 mg three times daily.

• Maximum 10 mg three times daily (30 mg daily).

• Give the first dose on rising, the second at midday and the third in the late afternoon, at least 4 hours before bedtime and not after 6 pm.

• Review benefit at 4 to 6 weeks; stop if there is no sustained symptomatic gain.

Hepatorenal syndrome, adult (off label, with albumin and octreotide). Midodrine 7.5 mg orally three times daily, titrated to 12.5 to 15 mg three times daily to raise mean arterial pressure by 10 to 15 mmHg, with octreotide 100 to 200 micrograms SC three times daily and albumin 20 to 40 g daily. Noradrenaline infusion is preferred in intensive care.

Intradialytic hypotension, adult (off label). 2.5 to 10 mg orally 30 to 60 minutes before dialysis.

Children. Not established.

Contraindications. Severe organic heart disease; acute kidney disease; urinary retention; phaeochromocytoma; thyrotoxicosis; persistent and excessive supine hypertension.

Warnings. Supine hypertension is the main risk; stop or reduce the dose if supine systolic pressure stays over 180 mmHg, and advise sleeping with the head of the bed raised 10 to 30 degrees. Piloerection, scalp pruritus and tingling are common. Urinary retention in men with prostate enlargement. Bradycardia, especially with other rate lowering drugs.

Adverse effects. Supine hypertension, piloerection, scalp tingling, urinary urgency or retention, paraesthesia, headache, chills.

Interactions. Additive pressor effect with other vasoconstrictors and sympathomimetics. Fludrocortisone adds to supine hypertension. Beta blockers, digoxin and other drugs that slow the heart add bradycardia. Alpha blockers and clonidine oppose the effect.

Special groups.

• Pregnancy: avoid unless essential; animal data show toxicity.

• Breastfeeding: avoid; no data.

• Older adults: start at 2.5 mg and titrate carefully; supine hypertension is more frequent.

• Kidney impairment: start 2.5 mg; the drug is cleared by the kidney, and acute kidney disease is a contraindication.

• Liver impairment: caution; the prodrug is activated in many tissues, with limited data.

Formulations. Tablets 2.5 mg, 5 mg and 10 mg.

Administration. Oral, with or without food, in the daytime only. Keep the interval between doses about 3 to 4 hours.

Baseline. Supine and standing blood pressure after 3 minutes, heart rate, renal function, prostate symptoms.

Monitoring. Supine and standing pressures at each dose change and at least every 3 to 6 months; heart rate; renal function annually; urinary symptoms.

Stopping. Stop if supine hypertension cannot be controlled, if there is no benefit, or if symptoms of urinary retention develop.

Common prescribing errors. Giving a late evening dose; ignoring supine pressures; combining with fludrocortisone without checking lying pressure; using it in kidney failure.